Relapse to drug abuse is a cardinal feature of drug addiction and perhaps the most difficult to treat. Cocaine users appear to be particularly vulnerable to relapse. Although the factors underlying relapse are not well understood, there is growing clinical and experimental evidence pointing to drug-associated environmental cures and re-exposure to the drug itself as important variables. During the past year we have begun a program to evaluate the impact of drug-associated cues and acute re-exposure to drug injections on relapse to cocaine use in a nonhuman primate model of drug self-administration. In this model, squirrel monkeys were trained to self-administer cocaine under a second-order schedule in which the completion of every tenth response produced a flash of light (brief stimulus) and the first 10-response unit completed after the elapse of 10 min produced both the brief stimulus and an i.v. injection of cocaine. High rates of responding, often exceeding 1 resp/sec, were maintained under these conditions by doses of cocaine ranging from 0.1 - 1.0 mg/kg/injection. Responding was virtually eliminated during a series of extinction sessions in which saline vehicle was substituted for cocaine and the brief stimulus was omitted. Following extinction, responding could be reinstated by injecting cocaine before the session independent of the subjects behavior, by restoring the brief stimulus previously associated with cocaine injections, or maximally by both. Under the latter condition, cocaine-induced reinstatement was dose- and time-dependent and could be blocked by the D1 dopamine antagonist SCH 39166, the D2 dopamine antagonist eticlopride, the D1/D2 antagonist cis-(Z)-flupenthixol. The results suggest that this model can provide a sensitive means for evaluating pharmacological and environmental factors contributing to relapse and for identifying candidate therapeutics to prevent its occurrence.